This Program Project grant application seeks to define the mechanisms of Pb toxicity in the skeleton. The investigators have evidence that the adverse effects of this heavy metal on bone and cartilage function contribute to diseases such as osteoporosis and hinder osteoporotic fracture healing. The Program Project is made up of four projects, two of which are cellular and molecular in nature, one is animal-based and one is clinical. Two cores are also proposed, an Administrative Core and a Histopathology Core. Project 1: Molecular mechanism of lead's effect on osteoclasts and osteoblasts; this project will examine how Pb influences the key regulatory genes controlling bone resorption and bone formation. Preliminary data have implicated osteoprotegrin (OPG), RANK ligand, and TRIP as the genes responsible. The project will have both in vitro and in vivo components. Project 2: Cellular and molecular effects of lead on chondrogenesis and cartilage differentiation; this research seeks to demonstrate that primordial regulators of chondrogenesis and cartilage differentiation; (i.e. the BMP's Indian hedgehog, PTHrP, etc.) are influenced in a complex way by Pb. Lead exposure leads to inappropriate skeletal development and predisposes affected individuals to osteoporosis. Project 3: Lead effects on skeletal stem cells and fracture healing; Project 3 will use an animal model to document that the findings in Project 1 and 2 are manifested in vivo. Additionally, this work will characterize the mechanism of the effect of Pb on hindering normal fracture healing. Project 4: Clinical diagnostic and therapeutic approaches to skeletal lead toxicity; this project extends the basic science investigations into a clinical trial. It seeks to determine if therapeutic approaches for osteoporosis are effective in Pb-containing skeletons and in controlling blood Pb levels. This Program Project will define novel molecular pathways to explain the adverse effects of Pb on bone and cartilage. The pathways will be examined and validated in animals, and ultimately the findings will be translated into clinical trials. This Program Project provides the opportunity to investigate the skeletal effects of Pb from "the bench" to the "bedside". It is unique in this regard.